Angiotensin Converting Enzyme Inhibitors and Angiotensin Receptor Blockers: A Promising Medication for Chronic Obstructive Pulmonary Disease?

Figures & data

Figure 1. The renin-angiotensin-aldosterone system.

Figure 2. Actions of RAS in COPD. (Lines ending with a perpendicular segment represent inhibitory pathways).

Figure 3. Impact of ACE inhibitors and ARBs on oxidative stress, proinflammatory signaling and proliferative effects induced by RAS activation. AT1 R: angiotensin II type 1 receptor, eNOS: endothelial nitric oxide synthase, IL: interleukin, NADPH: reduced form of nicotinamide adenine dinucleotide phosphate, NF-kB: transcription factor nuclear factor-kB, NO: nitric oxide,, ROS: reactive oxygen species, TGF-b1: transforming growth factor b1, TNF-a: tumor necrosis factor-a. (Lines ending with a perpendicular segment represent inhibitory pathways).

Table 1. Main studies that support a beneficial effect of RAS blockers in COPD patients.

Author (year)	No. of pts	Type of study	Results/findings
Mancini et al. [77] (2006)	5853	Retrospective	Either ACEi or ARBs and statins reduced both cardiovascular and pulmonary outcomes, with the largest benefits occurring with the combination of these drugs. This combination was associated with a reduction in COPD hospitalization (RR 0.66, 95% CI 0.51 to 0.85) and total mortality (RR 0.42, 95% CI 0.33 to 0.52) not only in the high cardiovascular risk cohort but also in the low cardiovascular risk cohort (RR 0.77, 95% CI 0.67 to 0.87, and RR 0.36, 95% CI 0.28 to 0.45, respectively)
Mortensen et al. [78] (2009)	11 212	Retrospective	ACEi/ARB use (0.55, 95% CI 0.46-0.66) and statin use (OR 0.51, 95% CI 0.40-0.64) were significantly associated with decreased 90-day mortality in subjects hospitalized with a COPD exacerbation
Paulin et al. [79] (2017)	4331	Retrospective	ARBs use seems to be associated with a lower mortality in COPD. The survival in the ARBs exposed group was 76% (CI 95% 0,69-0,81) and 71% (CI 95% 69–73%) in the non exposed group. The unadjusted HR for mortality was 0.85 (CI 95% 0.67-1.07, p  =  0.17) and the adjusted HR by propensity score was 0.63 (CI 95% 0.50-0.80, p < 0.001)
Petersen et al. [80] (2014)	1170	Observational	Among ever smokers without a baseline spirometric abnormality, rapid decline was associated with an increased risk for incident COPD (OR 1.88; p = 0.003). The use of ACEi at baseline examination was protective against rapid decline, particularly among those with comorbid cardiovascular disease, hypertension, or diabetes (OR 0.48, 0.48, and 0.12, respectively; p ≤0.02 for all analyses)
Ho et al. [81] (2014)	4204	Population-based cohort	COPD patients hospitalized for first-ever COPD exacerbation receiving ARB for a cardiovascular disease, had lower in-hospital mortality (OR: 0.61; 95% CI: 0.38-0.98)
Di Marco et al. [82] (2010)	21	Double-blind, cross-over study	Enalapril did not affect the ventilatory response to exercise in COPD patients, but improved work rate and O2 pulse
Curtis et al. [83] (2016)	80	Double-blind, placebo-controlled, parallel-group randomized controlled trial	Enalapril, together with a program of pulmonary rehabilitation, in patients without an established indication for ACEi, reduced the peak work rate response to exercise training
Zeng et al. [85] (2013)	220	Retrospective	ACEi and ARBs reduce mortality in elderly male COPD patients
Kim et al. [86] (2016)	375	Case-control	ACEi/ARBs reduce the risk of pneumonia in COPD patients (OR = 0.51, 95% CI 0.27-0.98, p = 0.04)
Parikh et al. [87] (2017)	4472	Population-based	RAS blockers are associated with slowed progression of percent emphysema on chest CT (p  = 0.03)
Ekstrom et al. [88] (2013)	2249	Prospective	COPD patients receiving RAS blockers showed trends towards decreased mortality (HR, 0.90; 95% CI, 0.79-1.04; P = 0.166)
Kanazawa et al. [89] (2003)	36	Randomized double blind controlled trial	Captopril reduces mPAP in ID/II carriers
Bertoli et al. [90] (1986)	9		Captopril reduces mPAP(p < 0.05), mean pulmonary wedge pressure (p < 0.05) and total pulmonary resistance in COPD patients with pulmonary hypertension

COPD: chronic obstructive pulmonary disease; pts: patients; ACEi: angiotensin converting enzyme inhibitors; ARB: angiotensin receptor blocker; RR: risk ratio; CI: confidence interval; OR: odds ratio; HR: hazard ratio; CT :computed tomography; mPAP: mean pulmonary artery pressure.

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